Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• Camptothecin reversibly interacts with the cleavable complex and subsequently induces DNA single strand breaks by interfering with the religation step (Hsiang, Y.-H. et al. Camptothecin induces protein-linked DNA DNA brasks via mammalian DNA topoisomerase I. J. Biol. Chem., 260:14873-14878, 1985; Porter, S. E. et al.
• campthotecin is poorly soluble in water, and therefore, it itself can not be formulated for the use of intravenous injection.
• a number of camptothecin derivatives were synthesized to improve anti-tumor activity, lactone stability in plasma and/or water solubility, and were tested clinically (Gerrits, C. J. H., de Jonge, M. J. et al. Topoisomerase I inhibitors: the relevance of prolonged exposure for clinical development. Br. J. Cancer, 76: 952-962, 1997; O'Leary, J. et al. Camptothecins: a review of their development and schedules of administration. Eur. J. Cancer, 34: 1500- 1508, 1988; Gerderblom, H. A.
• camptothecin derivatives include 9- nitrocamptothecin (Pantazis, P. et al. The role of pH and serum albmin in the metabolic conversion of 9-nitrocamptothecin to 9-aminocamptothecin by human hematopoietic and other cells. Eur. J. Hematol., 55:211-213, 1995; Loos, W. J. et al. Determination of the lactone and lactone plus carboxylate forms of 9-aminocamptothecin in human plasma by sensitive high-performance liquid chromatography with fluorescent detection. J.
• (C1-C10) alkyl optionally substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, mono-(Cl-C5) alkylamino, di-(Cl-C5) alkylamino and (C3-C7) cycloalkyl, a heterocyclic ring and aryl in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(Cl-C5) alkylamino and di-(Cl-C5) alkylamino;
• R 2 is hydrogen; amino; (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, mono- (C1-C5) alkylamino, di-(Cl-C5) alkylamino optionally substituted with one to three moieties independently selected from the group consisting
• X is oxygen or sulfur; and pharmaceutically acceptable salts thereof.
• a still further object of the present invention is to provide a process for the preparation of the above hexacyclic compounds.
• alkyl refers a straight or branched monovalent saturated aliphatic hydrocarbon group.
• C1-C10) alkyl means a straight chain or branched hydrocarbon chain having 1 to 10, preferably 1 to 8 carbon atom(s), e.g.
• alkoxy refers to the group -O-R', wherein R' is an alkyl group as defined above.
• (Cl-C5)alkoxy preferably means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methylbutoxy, 2,2-dimethylprppoxy and the like.
• halogen refers to fluoro, chloro, bromo and iodo.
• amino refers to the group -NH 2 and includes amino groups which are protected by a group known in the art such as a formyl, acetyl, trithyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, and the like. Preferably, it means -NH 2 .
• mono-alkylamino refers to the group -NH-R', wherein R' is an alkyl group as defined above, and includes amino groups which are protected by a group known in the art such as a formyl, acetyl, trithyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, and the like.
• mono-(Cl-C5)alkylamino preferably means N-methylamino, N- ethylamino, N-propylamino, N-isopropylamino, N-butylamino, N-(l- methylpropyl) amino, N-(2-methylpropyl)amino, N-pentylamino, and the like, more preferably N-ethylamino, N-propylamino, N-butylamino and the like.
• di-alkylamino refers to the group -NR'R", wherein R' and R" are (independently from each other) an alkyl group as defined above.
• "di-(Cl-C5)alkylamino” preferably means N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, N,N- diisopropylamino, N,N-dibutylamino, N-methyl-N-ethylamino, N-methyl-N- propylamino and the like, more preferably N,N-dimethylamino, N,N-diethylamino.
• (C3-C7)cycloalkyT means 3 to 7 membered ring, which do not contain any heteroatoms in the ring.
• Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, more preferably cyclopentyl and cyclohexyl.
• aryl means an aromatic carbocyclic group, i.e. a 6 or 10 membered aromatic or partially aromatic ring, e.g. phenyl, naphthyl or tetrahydronaphthyl, preferably phenyl or naphthyl, and most preferably phenyl.
• (Cl-C5)alkylthio refers to the group R'-S-, wherein R' is an (Cl-C5)alkyl as defined above, preferably methyl, ethyl, propyl, isopropyl and the like, more preferably methyl and ethyl.
• the expression “optionally substituted with” means that substitution can occur at one to three positions, preferably at one position, and, unless otherwise indicated, that the substituents are independently selected from the specified options.
• the acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid and the like.
• the base- addition salts include those derived from potassium, sodium, ammonium, and quarternary ammonium hydroxide, such as for example tetramethylammonium hydroxide.
• R 1 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, 3-methylbutyl, 2,2-dimethylpropyl,l-ethylpropyl, hexyl, 4-methylpentyl, 3,3-dimethylbutyl, heptyl, 2-methoxyethyl, 2-ethoxyethyl, 2- propoxylethyl, 3-methoxypropyl, 4-methoxybutyl, 2-hydroxyethyl, 3-hydroxypropyl, 4- hydroxybutyl, 5-hydroxypentyl, 2-fluoroethyl, 3-fluoropropyl, 4-fluorobutyl, 2- chloroethyl, 3-chloropropyl, 4-chlorobutyl, 2-(dimethylamino)ethyl, 3- (dimethylarnino)propyl, 2- (cyclohexyl
• R 1 is hydrogen; (C1-C10) alkyl, optionally substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, mono-(Cl-C5) alkylamino, di-(Cl-C5) alkylamino and (C3-C7) cycloalkyl, a heterocyclic ring and aryl in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(Cl-C5) alkylamino and di-(Cl-C5) alkylamino;
• R 2 is hydrogen; amino; (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkyl
• Preferred compounds of the present invention are those of formula [ 1 A] ,
• R 1 , R 3 and R 4 are as defined in claim 1 and pharmaceutically acceptable salts thereof.
• the invention preferably refers to compounds of formula [1A], wherein R 1 is hydrogen; or (C1-C8) alkyl optionally substituted with one or three moieties independently selected from the group consisting of (C1-C3) alkoxy, hydroxy, halogen, amino, mono-(Cl-C3) alkylamino, di-(Cl-C3) alkylamino, (C3-C7) cycloalkyl, a heterocyclic ring and aryl in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy and halogen; and R 3 and R 4 are hydrogen.
• R 1 in compounds of formula [1A] is (Cl-C8)alkyl, phenyl-(Cl-C8) alkyl, heterocyclic ring-(Cl-C8)alkyl, alkoxyphenyl(Cl- C8)alkyl or halogenphenyl(Cl-C8)alkyl, and most preferably R 1 in compounds of formula [1A] is methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1,1-dimethylethyl, 2-methylpropyl, 2,2-dimefhylpropyl, n-pentyl, 3-methylbutyl, 2- n-hexyl, 3,3-dimethylbutyl, n-heptyl, n- octyl, benzyl, phenethyl, 2-(dimefhylamino)efhyl, 2-(4-morpholino)ethyl,
• Preferred compound may be selected from the group consisting of: a) (9S)-l-butyl-9-ethyl-9-hydroxy-lH,12H- pyrano[3",4":6 7']indolizino[1 2 6,5]pyrido[4,3,2-de]quinazoline-
• the invention also refers to pharmaceutical compositions comprising a compound as described above as an active ingredient and a pharmaceutically acceptable carrier, especially those which are suitable for oral or parenteral administration.
• the invention relates to the use a compound as defined above for the preparation of medicaments, especially for the treatment of cell proliferative disorders and/or cancer, e.g. colorectal cancer, lung cancer, breast cancer, stomach cancer, cervical cancer and bladder cancer.
• the invention also refers to a method for treating a cell proliferative disorder, e.g. cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as described above.
• the method is especially useful for the treatment of solid tumors and cancers like colorectal cancer, lung cancer, breast cancer, stomach cancer, cervical cancer and bladder cancer.
• the invention also provide a process for producing a compound of formula [2] ,
• L 1 and L 2 are independently leaving group such as halogen, (Cl-C3)alkoxy optionally substituted by one to three halogen(s), phenyloxy optionally substituted by nitro group, succinimidyloxy or imidazole;
• Another process of the invention refers to a process for producing a compound of formula [5],
• R 1 , R 2 , R 3 and R 4 are the same as defined above, and R 5 is (C1-C5) alkanoyl, which comprises reacting a compound of the formula [3] or its salt,
• the invention also refers to a process for producing a compound of formula [1] as defined above or a pharmaceutically acceptable salt thereof,
• R 5 is (C1-C5) alkanoyl, to deacylation with a hydrazine or its derivative.
• Step A Oxidation of a compound of the formula [7] to prepare a compound of the formula [8],
• the oxidation of the above Step A is preferably carried out with a suitable oxidising reagent in a suitable solvent.
• suitable oxidising reagents are hydrogen peroxide such as aqueous hydrogen peroxide and hydrogen peroxide-urea complex, percarboxylic acid such as peracetic acid, perbenzoic acid or m-chloroperbenzoic acid as like, and suitable solvent are acetic acid, tetrahydrofuran, chloroform, dichloromethane, as like.
• the oxidation is conducted at the temperature between 0 to 100 °C for 1 to 10 hours.
• Step B Chlorination of a compound of the formula [8] to prepare a compound of the formula [9],
• the chlorination of the above Step B is preferably carried out with a suitable chlorinating reagent in a suitable solvent.
• Suitable chlorinating reagents are phosphoryl chloride, thionyl chloride, oxalyl chloride, Nilsmeier reagent as like, with the use of ⁇ , ⁇ - dimethyl formamide as a catalyst or solvent.
• Suitable solvents are chloroform, dichloromethane as like as well as ⁇ , ⁇ -dimethylformamide as mentioned the above.
• the reaction is conducted at the temperature 0 to 80 °C for 1 to 15 hours.
• Step C Addition of an amine R - ⁇ H 2 to a compound of the formula [9] to prepare a compound of the formula [10],
• Step C is preferably carried out in a suitable organic solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, chloroform, N, N- dimethyl formamide as like at the temperature from room temperature to 120 °C for a period of 15 minutes to 1 day.
• a suitable organic solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, chloroform, N, N- dimethyl formamide as like at the temperature from room temperature to 120 °C for a period of 15 minutes to 1 day.
• the reaction of the above Step D is preferably carried out with a reducing reagent in a suitable solvent in the presence of a suitable catalyst.
• Suitable reducing reagents are molecular hydrogen, or hydrogen source such as cyclohexadiene, formic acid, ammonium formate as like.
• Suitable solvents are e.g., methanol, ethanol, ethyl acetate, N,N-dimethyl formamide, 1,4-dioxane, and water with or without inorganic or organic acid such as 1 to 10 N aqueous hydrochloric acid, sulfonic acid, phosphonic acid, nitric acid, acetic acid, frifluoroacetic acid.
• the reaction of the above Step E is preferably carried out with a suitable reagent of the formula [7] and a suitable base in a suitable solvent.
• Suitable bases are typically trialkylamine such as triethylamine and diisopropylethylamine, aromatic amine such as pyridine and lutidines, and inorganic base such as sodium carbonate and sodium bicarbonate.
• Suitable solvents are chloroform, dichloromethane, acetonitrile, 1,4-dioxane, N,N-dimethyl formamide as like.
• the reaction is conducted typically at between -20 to 100 °C for a period from 5 minutes to 1 several days.
• Typical reagents of the formula [10] are phosgene, diphosgene, triphosgene, thiophosgene, carbonyl diimidazole, thiocarbonyl diimidazole, phenyl chloroformate, ethyl chloroformate, diphenyl carbonate and the like.
• Step F Reaction of a compound of the formula [3'] with a compound of the formula [6],
• Suitable bases are typically trialkylamine bases such as triethylamine and diisopropylethylamine, aromatic amine bases such as pyridine and lutidines, and inorganic bases such as sodium carbonate and sodium bicarbonate.
• Suitable acid catalysts are typically inorganic acids such as hydrochloric acid, sulfonic acid and nitric acid, organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid, and Lewis acid such as boron trifluoride, titanium tetrachloride and tin tetrachloride as like.
• Suitable solvents are chloroform, dichloromethane, acetonitrile, 1,4-dioxane, N,N-dimethyl formamide and the like. The reaction is conducted typically at between -20 to 100 °C for a period from 5 minutes to 1 several days.
• Step G Reaction (deacetylation) of a compound of the formula [2'] or [5'] with hydrazine to prepare a hexacyclic compound of the formula [1A] or [IB]
• the reaction of the above Step G is preferably carried out with hydrazine in a suitable solvent and at suitable temperature.
• the suitable solvent are typically methanol, ethanol, 1,4-dixane, N,N-dimethylformamide, dimethylsulfoxide and water as like.
• the reaction is conducted typically at between -20 to 100 °C for a period from 5 miutes to 1 several days.
• hexacyclic compounds of the formula [IB] can be prepared alternatively from a compound [2'] by processes illustrated in the following Scheme 2.
• R 2 is (Cl-C5)alkylthio amino, mono-(Cl-C5)alkylamino or di- (Cl-C5)alkylamino
• X is sulfur
• R 1 , R 3 and R 4 denote the same as those of the hexacyclic compounds of the formula [IB]
• R 11 is (Cl-C5)alkyl
• R 12 and R 13 are independently hydrogen or (Cl-C5)alkyl.
• Step I Oxidation of a compound of the formula [12] to prepare a compound of the formula [13],
• Step I The oxidation of the above Step I is preferably carried out with a suitable oxidising reagent in a suitable solvent.
• suitable oxidising reagents are peroxide such as aqueous hydrogen peroxide and hydrogen peroxide-urea complex, percarboxylic acid such as peracetic acid, perbenzoic acid or m-chloroperbenzoic acid, and persulfate such as OXONE®(DuPont, U.S.A.), and suitable solvents are acetic acid, tetrahydrofuran, chloroform, dichloromethane, and the like.
• the reaction is conducted at the temperature between 0 to 100 °C for 1 to 10 hours.
• Step J Addition of an amine of the formula HNR 12 R 13 to a compound of the formula [13] to prepare a compound of the formula [14],
• the manufacture of the pharmaceutically acceptable acid addition salts of the hexacyclic compounds of the formula [1] can be carried out by treating a free base of the hexacyclic compound of the formula [1] with an acid in a per se conventional procedure for the salt formation.
• therapeutically acceptable acids useful in the above process are inorganic acids (e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid) and organic acids (e. g. oxalic acid, acetic acid, formic acid, trifluoroacetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid, methanesulfonic acid).
• inorganic acids e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid
• organic acids e. g. oxalic acid, acetic acid, formic acid,
• the hexacyclic compounds of the formula [1] can be converted into the hydrates or solvates and their salts by various methods known to those skilled in the art.
• the hexacyclic compounds of the present invention are useful for the treatment of cancer. Accordingly, the present invention comprises the use of the above compounds for the manufacture of medicaments for the treatment of cancer and the corresponding pharmaceutical compositions which comprise a hexacyclic compound as defined above and a pharmaceutically acceptable carrier.
• the hexacyclic compounds of the present invention are effective at inhibiting or preventing the growth of tumors in premalignant and malignant cells and are useful for the treatment of carcinomas forming solid tumors, especially of colorectal cancer, lung cancer, breast cancer, stomach cancer, cervical cancer and bladder cancer.
• the hexacyclic compounds of the present invention can be used to treat such tumors, to retard the development of such tumors, and to prevent the increase in number of tumors.
• Carcinoma cells for assays are readily obtained from cells depositories such as the American Type Culture Collection (ATCC) or maybe isolated by skilled persons from cancer patients.
• ATCC American Type Culture Collection
• the type of cancer against which the hexacyclic compounds of this invention are most active is determined by the type of cells used in the assays.
• the proportion of cells which have become differentiated after addition of a test compound may be determined by known methods (i.e. measuring oxidative burst in HL-60 cells, an indicator of differentiation, by NBT(nitroblue tetrazolium). If 10% or more cells have differentiated, then the compound is regarded as having therapeutic activity.
• Antiproliferative activity assay was carried out as follows. A single suspension of tumor cells was inoculated to the serially diluted 96-well microtestplate. Then the testplate was incubated in the 5% CO 2 ambience at 37°C for 4 days (2 - 3x 10 3 cells/well). The degree of cell growth in a monolayer was measured by using WST-8 (Dojindo, Japan). IC 50 values of drugs against tumor cells were calculated as the concentration of drug yielding 50% OD of the control growth. The results are shown in the following Table 1.
• Compound A denotes (9S)-9-ethyl-9-hydroxy-l-phenethyl-lH,12H- pyrano[3",4":6 ⁇ indolizino[ 2 ⁇ 6,5]pyrido[4,3,2-de]quinazoline- 2,10,13(3H,9H,15H)-trione.
• Compound D denotes (9S)-9-efhyl-9-hydroxy-l-(3-methylbutyl)-2(3H)-thioxo-lH,12H- pyrano[3'',4":6',7']indolizino[ ,2':6,5]pyrido[4,3,2-de]quinazoline- 10,13(9H,15H)-dione.
• Compound E denotes (9S)-9-ethyl-9-hydroxy-2-methyl-l-pentyl-lH,12H- pyrano [3",4":6',7']indolizino [ l',2':6,5]pyrido [4,3,2-de] quinazoline- 10,13(9H,15H)-dione.
• Compound F denotes (9S)-9-ethyl-9-hydroxy-2-hydroxymefhyl-l-(3-methylbutyl)- lH,12H-pyrano[3",4":67']indolizino[l'2':6,5]pyrido[4,3,2-de]quinazoline- 10,13(9H,15H)-dione.
• SN-38 denotes 7-ethyl-lO-hydroxycamptothecin.
• excipients which maybe used include for example water, polyols, saccharose, invert sugar and glucose.
• excipients which may be used include for example water, alcohols, polyols, glycerine, and vegetable oils.
• excipients which may be used include for example natural or hardened oils, waxes, fats and semi-solid or liquid polyols.
• the daily dosage level of the hexacyclic compounds of the present invention is from 5 to 2,000 mg/m 2 when administered by either the oral or parenteral route.
• tablets or capsules can contain from 5 mg to 1,000 mg of active compound for single administration or two or more at a time as appropriate.
• the actual dosage can be weight and response of the particular patient.
• the following examples illustrate the preferred methods for the preparation of the hexacyclic compounds of the present invention, which are not intended to limit the scope of the invention thereto.
• This compound was prepared from (20S)-7-chloro-9-nitrocamptothecin 20-acetate of Reference Example 3.1 and N,N-dimethyl 1,3-diaminopropane according to a manner analogous to those of Reference Example 4.1.
• This compound was prepared from (20S)-7-chloro-9-nitrocamptothecin 20-acetate of Reference Example 3.1 and propylamine according to a manner analogous to those of Reference Example 4.1.
• This compound was prepared from (20S)-7-chloro-9-nitrocamptothecin 20-acetate of Reference Example 3.1 and benzylamine according to a manner analogous to those of Reference Example 4.1.
• This compound was prepared from (20S)-7-chloro-9-nitrocamptothecin 20-acetate of Reference Example 3.1 and phenethylamine according to a manner analogous to those of Reference Example 4.1.
• This compound was prepared from (20S)-7-chloro-9-nitrocamptothecin 20-acetate of Reference Example 3.1 and 3-phenylpropylamine according to a manner analogous to those of Reference Example 4.1.
• This compound was prepared from (20S)-7-chloro-9-nitrocamptofhecin 20-acetate of Reference Example 3.1 and 3-(2-aminoethyl)pyridine according to a manner analogous to those of Reference Example 4.1.
• This compound was prepared from (20S)-7-chloro-9-nitrocamptothecin 20-acetate of Reference Example 3.1 and isobutylamine according to a manner analogous to those of Reference Example 4.1.
• This compound was prepared from (20S)-7-chloro-9-nitrocamptothecin 20-acetate of Reference Example 3.1 and butylamine according to a manner analogous to those of Reference Example 4.1.
• This compound was prepared from (20S)-7-chloro-9-nitrocamptothecin 20-acetate of Reference Example 3.1 and ethylamine according to a manner analogous to those of Reference Example 4.1.
• This compound was prepared from (20S)-7-[3-(dimethylamino)propylamino]-9- nitrocamptothecin 20-acetate of Reference Example 4.3 according to a manner analogous to those of Example 5.1.
• This compound was prepared from (20S)-9-nitro-7-(pentylamino)camptofhecin 20- acetate of Reference Example 4.1 according to a manner analogous to those of Reference Example 5.1.
• This compound was prepared from (20S)-7-ethylamino-9-nitrocamptothecin 20- acetate of Reference Example 4.16 according to a manner analogous to those of Reference Example 5.1.
• This compound was prepared from (20S)-7-[2-(4-fluorophenyl)ethylamino]-9- nitrocamptothecin 20-acetate of Reference Example 4.19 according to a manner analogous to those of Reference Example 5.1.
• This compound was prepared from (20S)-7-(3,3-dimethylbutylamino)-9- nitrocamptothecin 20-acetate of Reference Example 4.21 according to a manner analogous to those of Reference Example 5.1.
• This compound was prepared from (20S)-7-(3-methylbutylamino)-9- nitrocamptothecin 20-acetate according of Reference Example 4.10 to a manner analogous to those of Reference Example 5.1.
• This compound was prepared from (20S)-7-(2-hydroxyethylamino)-9- nitrocamptothecin 20-acetate of Reference Example 4.23 according to a manner analogous to those of Reference Example 5.1.
• the preparation method comprises of the following two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(2- morpholinoethyl)aminocamptothecin 20-acetate of Reference Example 5.2 according to a manner analogous to those of Example 1.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(propylamino)camptothecin 20-acetate of Reference Example 5.4 according to a manner analogous to those of Example 1.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(benzylamino)camptothecin 20-acetate of Reference Example 5.9 according to a manner analogous to those of Example 1.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(3- phenylpropylamino)camptothecin 20-acetate of Reference Example 5.6 according to a manner analogous to those of Example 1.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7- [2-(pyridin-2- yl) ethylamino] camptothecin 20-acetate of Reference Example 5.7 according to a manner analogous to those of Example 1.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7- [2- (pyridin-3- yl)ethylamino] camptothecin 20-acetate of Reference Example 5.8 according to a manner analogous to those of Example 1.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(3- methylbutylamino)camptothecin 20-acetate of Reference Example 5.21 according to a manner analogous to those of Example 1.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(2- methylpropylamino) camptothecin 20-acetate of Reference Example 5.12 according to a manner analogous to those of Example 1.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(hexylamino)camptothecin
• This compound was prepared from (20S)- 9-amino-7-(3- methylbutylamino)camptofhecin 20-acetate of Reference Example 5.21 according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-ammo-7-(heptylamino)camptothecin 20-acetate of Reference Example 5.10 according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(hexylamino)camptothecin 20-acetate of Reference Example 5.13 according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(pentylamino)camptothecin 20-acetate of Reference Example 5.14 according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(ethylamino)camptothecin 20-acetate of Reference Example 5.15 according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-[2-(4- methoxyphenyl) ethylamino] camptothecin 20-acetate of Reference Example 5.16 according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-[2-(4- chlorophenyl)ethylamino] camptothecin 20-acetate of Reference Example 5.17 according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-[2-(4- fluorophenyl)ethylamino] camptothecin 20-acetate of Reference Example 5.18 according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-[2-(4- fluorophenyl)ethylamino]camptothecin 20-acetate of Reference Example 5.18 and trimethyl orthoacetate according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(l- methylethylamino) camptothecin 20-acetate of Reference Example 5.19 according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(3,3- dimethylbutylamino)camptothecin 20-acetate of Reference Example 5.20 according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(3- methylbutylamino)camptothecin 20-acetate of Reference Example 5.21 and tetramefhyl orthocarbonate according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(3- methylbutylamino)camptothecin 20-acetate of Reference Example 5.21 andtriethyl orthopropionate according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20RS)- 9-amino-10-methyl-7- (pentylamino) camptothecin 20-acetate of Reference Example 5.22 according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(2- hydroxyethylamino)camptothecin 20-acetate of Reference Example 5.23 according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (205)- 9-amino-7-(2- hydroxyethylamino)camptothecin 20-acetate of Reference Example 5.23 and trimethyl orthoacetate according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(pentylamino)camptothecin 20-acetate of Reference Example 5.14 and trimethyl orthoacetate according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(pentylamino)camptothecin 20-acetate of Reference Example 5.14 and triethyl orthopropionate according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(pentylamino)camptothecin 20-acetate of Reference Example 5.14 and trimethyl orthobutyrate according to a manner analogous to those of Example 2.1 in two steps via compound (a).
• the preparation method comprises of the following two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(2- methylpropylamino) camptothecin 20-acetate of Reference Example 5.12 according to a manner analogous to those of Example 3.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(3- methylbutylamino)camptothecin 20-acetate of Reference Example 5.21 according to a manner analogous to those of Example 3.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(3- methylbutylamino)camptothecin 20-acetate of Reference Example 5.21 and chloroacetyl chloride according to a manner analogous to those of Example 3.1 in two steps via compound (a).
• the preparation method comprises of the following three steps via compounds (a) and (b).
• the preparation method comprises of the following two steps via compound (a).
• the preparation method comprises of the following two steps via compound (a).
• the preparation method comprises of the following two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7- (phenethylamino)camptothecin 20-acetate of Reference Example 5.5 according to a manner analogous to those of Example 7.1 in two steps via compound (a).
• This compound was prepared from (20S)- 9-amino-7-(pentylamino)camptothecin 20-acetate of Reference Example 5.14 according to a manner analogous to those of Example 7.1 in two steps via compound (a).
• the preparation method comprises of the following two steps via compound (a).
• Example 7.1 (95)-9-Acetoxy-9-ethyl-l-(3-mefhylbutyl)-2(3H)-thioxo-lH,12H- pyrano[3",4":6 , ,7']indolizino[ ,2':6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione (190 mg, 0.36 mmol) of Example 7.1 (a) was dissolved in dry dichloromethane (10 ml) in a sealed tube.
• This compound was prepared from (9S)-9-acetoxy-9-ethyl-l-(3-methylbutyl)- 2(3H)-thioxo-lH,12H-pyrano[3",4":6',7']indolizino[l',2':6,5] ⁇ yrido[4,3,2- de]quinazoline-10,13(9H,15H)-dione of Example 7.1 (a) and ethyl iodide according to a manner analogous to those of Example 8.1 in two steps via compound (a).
• the preparation method comprises of the following three steps via compounds (a) and (b).
• the following tablets may be prepared by conventional methods:

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